Insight into Parkinson's Disease from Yeasts: Combined impact of covalent modifications & familial mutations on α‐synuclein

Abstract

Parkinson's Disease (PD) is a neurodegenerative disorder linked to the loss of dopaminergic neurons in the midbrain. A key pathological marker of PD is the presence of Lewy bodies, which are mainly composed of misfolded α‐synuclein protein. α‐synuclein is a highly post‐translationally modified protein. While phosphorylation and nitration of α‐synuclein are well studied in the context of PD pathology, less is known about sumoylation, which is proposed to be neuroprotective based on limited studies. The majority of sumoylation takes place on the lysine‐96 and lysine‐102 sites of α‐synuclein, and it increases the protein's solubility. The goal of this research was to better understand the role of sumoylation in regulating α‐synuclein toxicity, and we performed four studies towards it. First, we evaluated the effects of blocking sumoylation on α‐synuclein in the well‐established budding yeast model for PD and found that α‐synuclein becomes more aggregated, gains toxicity, and loses localization at the plasma membrane. Second, we evaluated the effects of altering sumoylation pathways by using yeast strains with reduced (ulp1ts) or excessive sumoylation (smt3ts), and found that α‐synuclein aggregates more with reduced sumoylation, but becomes less toxic with increased sumoylation. Third, we asked how altering phosphorylation of α‐synuclein would alter sumoylation's protective role and found that blocking phosphorylation (in α‐synuclein already blocking sumoylation) reduced the protein's toxicity. Finally, we began evaluating whether blocking sumoylation and altering phosphorylation on familial PD mutant versions of α‐synuclein would exacerbate its toxicity. We found preliminary evidence that the toxicity of the A53T mutation increases when sumoylation is blocked. In the future, we will conduct further studies to understand how sumoylation affects other variants and modifications of α‐synuclein.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.